Abstract LSUHSC CARC Research Component 3: Alcohol Use Disorder & Associated Neurological Symptoms of Cognitive Dysfunction and Pain Alcohol use disorder (AUD) is characterized by neurological deficits, negative affective states, and a profound escalation of drinking. The cognitive and behavioral deficits associated with excessive drinking are attributed to functional and persistent changes to neuronal circuitry. Chronic alcohol induced-cognitive impairments are associated with selective central nervous system damage in areas such as the prefrontal cortex (PFC). Excessive alcohol exposure also damages the peripheral nervous system to produce a characteristic neuropathy, and the resulting hyperalgesia (increased pain sensitivity) is hypothesized to potentiate negative reinforcement processes to increase motivation for alcohol. Alcohol use also represents a major exacerbating factor for human immunodeficiency virus (HIV) disease. Even in the post-antiretroviral therapy (ART) era neurocognitive deficits remain prevalent in persons living with HIV (PLWH). HIV-associated neurocognitive disorder (HAND) and co-occurring AUD can exacerbate these deficits. PLWH also suffer from chronic pain, which disrupts physical and emotional function, interferes with ART adherence, and doubles the chance of virologic failure. Pain symptoms in PLWH are associated with specific changes in the brain and correspondingly associates with numerous psychosocial factors in this population, including depression. While cognitive deficits and pain are closely linked in PLWH, few studies have examined the stress-related neurobiological factors that drive these interactions or how alcohol and HIV promote this process. The PFC represents and executes the highest forms of goal-directed behavior, and its function is compromised in motivational disorders such as AUD. As a potential neurobiological correlate of pain and cognitive impairment in PLWH, preclinical studies from our group and others have implicated a functional potentiation of glucocorticoid receptor (GR) signaling in association with excessive alcohol drinking, cognitive dysfunction, and chronic pain. Heightened GR signaling and altered excitability of vulnerable cognition- and pain-related brain areas such as the PFC may thus represent a unifying mechanism contributing to these pathologies. Finally, emerging evidence suggests that Western diets commonly consumed in the United States worsen both neurocognitive and pain symptomatology. Thus, the neurobiological interaction of excessive alcohol drinking, cognition, and pain in the context of Western diet consumption represents a critically underexplored area of HIV research in the public interest. Our overarching hypothesis is that excessive drinking and HIV/ART exposure in individuals consuming a Western diet additively produce cognitive deficits and hyperalgesia in PLWH in association with increased glucocorticoid signaling and hyperexcitability within the PFC. We will examine these factors using a bidirectional translational experimental design incorporating human and nonhuman primate models.